The overall goal of this project is to develop antibody therapy and prophylaxis to treat and prevent life-threatening flavivirus infections. West Nile virus is the focus of Phase I studies. Our working hypothesis is that high titer anti-envelope protein antibodies can protect humans against flaviviruses. Passive immunization is an accepted medical practice that can protect against infection. Immunizing animals with a proprietary recombinant West Nile virus envelope protein antigen induces high titer antibodies. These antibodies protect mice from a lethal dose of West Nile virus when administered i.p. to natve or infected mice. Protective anti-envelope protein antibodies will be produced using standard equine immunization and antibody purification protocols. IgG antibody, F(ab')2 and Fab administered i.v. or i.c.v will be evaluated in a mouse model of neurotropic WN virus infection. Phase I experiments will also begin developing neutralizing antibodies to related flavivirus envelope proteins. In Phase II, we expect to obtain preclinical data on an equine antibody preparation to protect humans and animals from West Nile virus infection; produce protective antibodies for related flaviviruses; and develop humanized anti-envelope protein monoclonal antibodies. This project will provide clinicians, public health officials, and veterinarians with new means to manage flavivirus virus outbreaks.